NOVEL 4-CYANO, 4-AMINO, AND 4-AMINOMETHYL DERIVATIVES OF PYRAZOLO[1,5-a]PYRIDINES, PYRAZOLO[1,5-c]PYRIMIDINES AND 2H-INDAZOLE COMPOUNDS AND 5-CYANO, 5-AMINO, AND 5-AMINOMETHYL DERIVATIVES OF IMIDAZO[1,2-a]PYRIDINES, AND IMIDAZO[1,5-a]PYRAZINES AS CYCLIN DEPENDENT KINASE INHIBITORS

ABSTRACT

In its many embodiments, the present invention provides a novel class of 4-cyano, 4-amino, and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and 2H-Indazole compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,5-a]pyrazine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

RELATED APPLICATIONS

The present application is a divisional of co-pending application U.S.Ser. No. 11/514,548, filed Aug. 31, 2006, which claims the benefit ofpriority to U.S. Provisional Application No. 60/715,621, filed Sep. 9,2005, each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to 4-cyano, 4-amino, and 4-aminomethylderivatives of pyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and2H-Indazole compounds and 5-cyano, 5-amino, and 5-aminomethylderivatives of imidazo[1,2-a]pyridine and imidazo[1,5-a]pyrazinecompounds useful as protein kinase inhibitors, pharmaceuticalcompositions containing the compounds, and methods of treatment usingthe compounds and compositions to treat diseases such as, for example,cancer, inflammation, arthritis, viral diseases, neurodegenerativediseases such as Alzheimer's disease, cardiovascular diseases, andfungal diseases.

BACKGROUND OF THE INVENTION

The cyclin-dependent kinases (CDKs) are serine/threonine proteinkinases, which are the driving force behind the cell cycle and cellproliferation. Individual CDK's, such as, CDK1, CDK2, CDK3, CDK4, CDK5,CDK6 and CDK7, CDK8 and the like, perform distinct roles in cell cycleprogression and can be classified as either G1, S, or G2M phase enzymes.Uncontrolled proliferation is a hallmark of cancer cells, andmisregulation of CDK function occurs with high frequency in manyimportant solid tumors. CDK2 and CDK4 are of particular interest becausetheir activities are frequently misregulated in a wide variety of humancancers. CDK2 activity is required for progression through G1 to the Sphase of the cell cycle, and CDK2 is one of the key components of the G1checkpoint. Checkpoints serve to maintain the proper sequence of cellcycle events and allow the cell to respond to insults or toproliferative signals, while the loss of proper checkpoint control incancer cells contributes to tumorgenesis. The CDK2 pathway influencestumorgenesis at the level of tumor suppressor function (e.g. p52, RB,and p27) and oncogene activation (cyclin E). Many reports havedemonstrated that both the coactivator, cyclin E, and the inhibitor,p27, of CDK2 are either over—or underexpressed, respectively, in breast,colon, nonsmall cell lung, gastric, prostate, bladder, non-Hodgkin'slymphoma, ovarian, and other cancers. Their altered expression has beenshown to correlate with increased CDK2 activity levels and poor overallsurvival. This observation makes CDK2 and its regulatory pathwayscompelling targets for the development years, a number of adenosine5′-triphosphate (ATP) competitive small organic molecules as well aspeptides have been reported in the literature as CDK inhibitors for thepotential treatment of cancers. U.S. Pat. No. 6,413,974, col. 1, line23-col. 15, line 10 offers a good description of the various CDKs andtheir relationship to various types of cancer.

CDK inhibitors are known. For example, flavopiridol (Formula I) is anonselective CDK inhibitor that is currently undergoing human clinicaltrials, A. M. Sanderowicz et al, J. Clin. Oncol. (1998) 16, 2986-2999.

Other known inhibitors of the CDKs include, for example, olomoucine (J.Vesely et al, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I.Meijer et al, Eur. J. Biochem., (1997) 243, 527-536). U.S. Pat. No.6,107,305 describes certain pyrazolo[3,4-b]pyridine compounds as CDKinhibitors. An illustrative compound from the '305 patent has theFormula II:

K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162disclose certain aminothiazole compounds as CDK inhibitors.

Pyrazolopyrimidines are known. For Example, WO92/18504, WO02/50079,WO95/35298, WO02/40485, EP94304104.6, EP0628559, (equivalent to U.S.Pat. Nos. 5,602,136, 5,602,137 and 5,571,813), U.S. Pat. No. 6,383,790,WO04/022561, WO04/026229, WO04/022559, WO04/022062, WO04/022560, Chem.Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med.Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 disclosevarious pyrazolopyrimidines.

Imidazopyrazines are also known. For Example, WO04/026877 andWO04/026310 disclose various imidazopyrazines

wherein: R¹ is H, halogen, or alkyl.

Additionally, Imidazopyridines and pyrazolopyridines are known. ForExample, WO04/026867 discloses various imidazopyridines and WO04/026872discloses various pyrazolopyridines

wherein R⁴ does not include a cyano or amino substituent.

Benzimidazoles are known. For example, U.S. Pat. No. 6,897,208 disclosesvarious benzimidazoles.

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with CDKs. It is,therefore, an object of this invention to provide compounds useful inthe treatment or prevention or amelioration of such diseases anddisorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class of4-cyano, 4-amino, and 4-aminomethyl derivatives ofpyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and 2H-Indazolecompounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives ofimidazo[1,2-a]pyridine and imidazo[1,5-a]pyrazine compounds asinhibitors of cyclin dependent kinases, methods of preparing suchcompounds, pharmaceutical compositions comprising one or more suchcompounds, methods of preparing pharmaceutical formulations comprisingone or more such compounds, and methods of treatment, prevention,inhibition or amelioration of one or more diseases associated with theCDKs using such compounds or pharmaceutical compositions.

In one aspect, the present application discloses a compound, orpharmaceutically acceptable salts or solvates of said compound, saidcompound having the general structure shown in anyone of FormulasIII-VII:

wherein:

Y is selected from the group consisting of CN, NH₂, and CH₂NH₂;

R¹ is selected from the group consisting of H, halogen, R⁹, NH₂, CN,alkyl, alkenyl, alkynyl, aryl, heteroaryl, CF₃, heterocyclylalkyl,arylalkyl, heteroarylalkyl, heterocyclyalkylalkyl, cycloalkyl,cycloalkylalkyl, C(O)OR⁴, alkyl substituted with 1-6 R⁹ groups which canbe the same or different and are independently selected from the list ofR⁹ shown later below,

wherein the aryl in the above-noted definitions for R¹ can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of halogen, CN, NH₂, —OR⁵, SR⁵, —CH₂OR⁵,—C(O)R⁵, —SO₃H, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —NR⁵R⁶, —C(O)NR⁵R⁶, —CF₃, and—OCF₃;

R² is selected from the group consisting of H, halogen, —NR⁵R⁶,—C(O)OR⁴, —C(O)NR⁵R⁶, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl,

wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R² andheterocyclyl moieties whose structures are shown immediately above forR² can be unsubstituted or optionally independently substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, CF₃, CN, —OCF₃, —(CR⁴R⁵)_(n)OR⁵,—OR⁵, —R⁵OR⁵, —NR⁵R⁶, —(CR⁴R⁵)_(n)NR⁵R⁶, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R⁶,—SR⁶, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R⁶;

R₃ is selected from the group consisting of a halogen, CN, amino,alkylamino, cycloalkylamino, arylalkylamino, heteroarylamino,heteroarylalkylamino, hydroxyalkylamino, heterocycloalkylalkylamino,wherein each of said amino, alkylamino, cycloalkylamino, arylalkylamino,heteroarylamino, heteroarylalkylamino, hydroxyalkylamino, andheterocycloalkylalkylamino can be unsubstituted or optionallyindependently substituted with one or more moieties, which can be thesame or different, each moiety being independently selected from thegroup consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, heteroarylalkyl, heterocycloalkylalkyl,cycloalkylalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R⁶, —C(R⁴R⁵)_(n)OR⁵, —C(O₂)R⁵,—C(O)R⁵, —C(O)NR⁵R⁶, —SR⁶, —S(O₂)R⁷, —S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶;

R⁴ is H, halogen, CN or alkyl;

R⁵ is H or alkyl;

R⁶ is selected from the group consisting of H, alkyl, aryl, arylalkyl,cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, whereineach of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclolalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, CF₃, OCF₃, CN, —OR⁵,—NR⁵R¹⁰, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R¹⁰,—SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R¹⁰;

R¹⁰ is selected from the group consisting of H, alkyl, aryl, arylalkyl,cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, whereineach of said alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl,heteroaryl, and heteroarylalkyl can be unsubstituted or optionallysubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of halogen, alkyl, aryl, cycloalkyl, CF₃, OCF₃, CN, —OR⁵,—NR⁴R⁵, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)NR⁴R⁵, —C(O)R⁵,—SO₃H, —SR⁵, —S(O₂)R⁷, —S(O₂)NR⁴R⁵, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁴R⁵; optionally (i) R⁵ and R¹⁰ in the moiety —NR⁵R¹⁰, or(ii) R⁵ and R⁶ in the moiety —NR⁵R⁶, may be joined together to form acycloalkyl or heterocycloalkyl moiety, with each of said cycloalkyl orheterocycloalkyl moiety being unsubstituted or optionally independentlybeing substituted with one or more R⁹ groups;

R⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl,heterocycloalkyl, heteroaryl, arylalkyl and heteroarylalkyl, whereineach of said alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,arylalkyl and heteroarylalkyl, for R⁷ can be unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from thegroup consisting of halogen, alkyl, aryl, cycloalkyl, CF₃, OCF₃, CN,—OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵, —C(O)NR⁵R¹⁰, —C(O)R⁵, —SR¹⁰,—S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰, —N(R⁵)C(O)R¹⁰ and—N(R⁵)C(O)NR⁵R¹⁰;

R⁸ is selected from the group consisting of R⁶, —C(O)NR⁵R¹⁰, —CH₂OR⁴,—C(O)OR⁶, —C(O)R⁷and —S(O₂)R⁷;

R⁹ is selected from the group consisting of halogen, —CN, —NR⁵R⁶,—(CH₂)_(n)OR⁴, —C(O₂)R⁶, —C(O)NR⁵R⁶, —OR⁶, —SR⁶, —S(O₂)R⁷, —S(O₂)NR⁵R⁶,—N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶;

m is 0 to 4; and

n is 1 to 4.

The compounds of Formulas III-VII can be useful as protein kinaseinhibitors and can be useful in the treatment and prevention ofproliferative diseases, for example, cancer, inflammation and arthritis.They may also be useful in the treatment of neurodegenerative diseasessuch as Alzheimer's disease, cardiovascular diseases, viral diseases andfungal diseases.

DETAILED DESCRIPTION

In one embodiment, the present invention disclosesPyrazolo[1,5-a]pyridine compounds which are represented by structuralFormula III or a pharmaceutically acceptable salt or solvate thereof,wherein the various moieties are as described above.

In another embodiment, the present invention disclosesPyrazolo[1,5-c]pyrimidine compounds which are represented by structuralFormula IV or a pharmaceutically acceptable salt or solvate thereof,wherein the various moieties are as described above.

In yet another embodiment, the present invention disclosesImidazo[1,2-a]pyridine compounds which are represented by structuralFormula V or a pharmaceutically acceptable salt or solvate thereof,wherein the various moieties are as described above.

In another embodiment, the present invention disclosesImidazo[1,5-a]pyrazine compounds, which are represented by structuralFormula VI or a pharmaceutically acceptable salt or solvate thereof,wherein the various moieties are as described above.

In still another embodiment, the present invention discloses 2H-Indazolecompounds, which are represented by structural Formula VII or apharmaceutically acceptable salt or solvate thereof, wherein the variousmoieties are as described above.

An inventive group of compounds are shown in Table 1.

TABLE 1

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, 2-butenyl and 3-methylbutenyl. The term “substitutedalkenyl” means that the alkenyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl. methylbutenyl. “Alkynyl” means an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and which may bestraight or branched and comprising about 2 to about 15 carbon atoms inthe chain. Preferred alkynyl groups have about 2 to about 12 carbonatoms in the chain; and more preferably about 2 to about 4 carbon atomsin the chain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl, are attached to a linear alkynyl chain. “Loweralkynyl” means about 2 to about 6 carbon atoms in the chain which may bestraight or branched. Non-limiting examples of suitable alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term“substituted alkynyl” means that the alkynyl group may be substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofalkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— andY₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, and aralkyl.

“Heterocyclyl” or “Heterocycloalkyl” means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls or heterocycloalkyls contain about 5 to about 6ring atoms. The prefix aza, oxa or thia before the heterocyclyl orheterocycloalkyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. Any —NH in aheterocyclyl ring may exist protected such as, for example, as an—N(Boc), —N(CBz), —N(Tos) group and the like; such protected moietiesare also considered part of this invention. The heterocyclyl can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein. The nitrogen orsulfur atom of the heterocyclyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl.

The bond to the parent moiety is through the carbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or Formula of this invention, its definitionon each occurrence is independent of its definition at every otheroccurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor, which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of this invention or a salt and/or solvatethereof. A discussion of prod rugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the CDK(s) and thus producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect.

The compounds of this invention can form salts, which are also withinthe scope of this invention. Reference to a compound of this inventionherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic salts formed with inorganic and/or organic acids, as well asbasic salts formed with inorganic and/or organic bases. In addition,when a compound of this invention contains both a basic moiety, such as,but not limited to a pyridine or imidazole, and an acidic moiety, suchas, but not limited to a carboxylic acid, zwitterions (“inner salts”)may be formed and are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of this invention may be formed, for example, byreacting a compound of this invention with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization. Acids(and bases) which are generally considered suitable for the formation ofpharmaceutically useful salts from basic (or acidic) pharmaceuticalcompounds are discussed, for example, by S. Berge et al, Journal ofPharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. ofPharmaceutics (1986) 33 201-217; Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; in The Orange Book(Food & Drug Administration, Washington, D.C. on their website); and P.Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of PharmaceuticalSalts: Properties, Selection, and Use, (2002) Int'l. Union of Pure andApplied Chemistry, pp. 330-331. These disclosures are incorporatedherein by reference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of this invention, and salts, solvates and prodrugs thereof,may exist in their tautomeric form (for example, as an amide or iminoether). All such tautomeric forms are contemplated herein as part of thepresent invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of this invention can beinhibitors of protein kinases such as the cyclin dependent kinases(CDKs), for example, CDC2 (CDK1), CDK2, CDK4, CDK5, CDK6, CDK7 and CDK8.The novel compounds of this invention are expected to be useful in thetherapy of proliferative diseases such as cancer, autoimmune diseases,viral diseases, fungal diseases, neurological/neurodegenerativedisorders, arthritis, inflammation, anti-proliferative (e.g., ocularretinopathy), neuronal, alopecia and cardiovascular disease. Many ofthese diseases and disorders are listed in U.S. Pat. No. 6,413,974 citedearlier, the disclosure of which is incorporated herein.

More specifically, the compounds of this invention can be useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing: carcinoma, including that of the bladder, breast, colon,kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin,including squamous cell carcinoma;

hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma and Burkett's lymphoma;

hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia;

tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma;

tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma and schwannomas; and

other tumors, including melanoma, seminoma, teratocarcinoma,osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroidfollicular cancer and Kaposi's sarcoma.

Due to the key role of CDKs in the regulation of cellular proliferationin general, inhibitors could act as reversible cytostatic agents whichmay be useful in the treatment of any disease process which featuresabnormal cellular proliferation, e.g., benign prostate hyperplasia,familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis,pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosisfollowing angioplasty or vascular surgery, hypertrophic scar formation,inflammatory bowel disease, transplantation rejection, endotoxic shock,and fungal infections.

Compounds of this invention may also be useful in the treatment ofAlzheimer's disease, as suggested by the recent finding that CDK5 isinvolved in the phosphorylation of tau protein (J. Biochem, (1995) 117,741-749).

Compounds of this invention may induce or inhibit apoptosis. Theapoptotic response is aberrant in a variety of human diseases. Compoundsof this invention, as modulators of apoptosis, will be useful in thetreatment of cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus, erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

Compounds of this invention, as inhibitors of the CDKs, can modulate thelevel of cellular RNA and DNA synthesis. These agents would therefore beuseful in the treatment of viral infections (including but not limitedto HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barrvirus, Sindbis virus and adenovirus).

Compounds of this invention may also be useful in the chemoprevention ofcancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

Compounds of this invention may also be useful in inhibiting tumorangiogenesis and metastasis.

Compounds of this invention may also act as inhibitors of other proteinkinases, e.g., protein kinase C, her2, raf 1, MEK1, MAP kinase, EGFreceptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abland thus be effective in the treatment of diseases associated with otherprotein kinases.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition associated with the CDKs byadministering a therapeutically effective amount of at least onecompound of this invention, or a pharmaceutically acceptable salt orsolvate of said compound to the mammal.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of this invention. An especially preferred dosage is about 0.01to 25 mg/kg of body weight/day of a compound of this invention, or apharmaceutically acceptable salt or solvate of said compound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more of anti-cancertreatments such as radiation therapy, and/or one or more anti-canceragents selected from the group consisting of cytostatic agents,cytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil); anti-metabolites (such asmethoxtrexate); alkylating agents (such as temozolomide (TEMODAR™ fromSchering-Plough Corporation, Kenilworth, N.J.), cyclophosphamide);Farnesyl protein transferase inhibitors (such as, SARASAR™(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide,or SCH 66336 from Schering-Plough Corporation, Kenilworth, N.J.),tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals),L778,123 (a farnesyl protein transferase inhibitor from Merck & Company,Whitehouse Station, N.J.), BMS 214662 (a farnesyl protein transferaseinhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, N.J.);signal transduction inhibitors (such as, Iressa (from Astra ZenecaPharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodiesto EGFR (e.g., C225), GLEEVEC™ (C-abl kinase inhibitor from NovartisPharmaceuticals, East Hanover, N.J.); interferons such as, for example,intron (from Schering-Plough Corporation), Peg-Intron (fromSchering-Plough Corporation); hormonal therapy combinations; aromatasecombinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN™ from Sanofi-Synthelabo Pharmaeuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17□-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, orHexamethylmelamine.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange. For example, the CDC2 inhibitor olomucine has been found to actsynergistically with known cytotoxic agents in inducing apoptosis (J.Cell Sci., (1995) 108, 2897. Compounds of this invention may also beadministered sequentially with known anticancer or cytotoxic agents whena combination formulation is inappropriate. The invention is not limitedin the sequence of administration; compounds of this invention may beadministered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Accordingly, in an aspect, this invention includes combinationscomprising an amount of at least one compound of this invention, or apharmaceutically acceptable salt or solvate thereof, and an amount ofone or more anti-cancer treatments and anti-cancer agents listed abovewherein the amounts of the compounds/treatments result in desiredtherapeutic effect.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays, which are described later have been carried outwith the compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions, whichcomprise at least one of the compounds of this invention, or apharmaceutically acceptable salt or solvate of said compound and atleast one pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of this invention, or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of this invention, or a pharmaceutically acceptablesalt or solvate of said compound and an amount of at least oneanticancer therapy and/or anti-cancer agent listed above, wherein theamounts of the two or more ingredients result in desired therapeuticeffect.

The invention disclosed herein is exemplified by the followingpreparations and examples, which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹ spectra were obtained on either a VarianVXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz)and are reported as ppm down field from Me₄Si with number of protons,multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min—10% CH₃CN, 5 min—95% CH₃CN, 7 min—95% CH₃CN, 7.5min—10% CH₃CN, 9 min—stop. The retention time and observed parent ionare given.

The following solvents, reagents, conditions, and techniques may bereferred to by their abbreviations:

-   Thin layer chromatography: TLC-   dichloromethane: CH₂Cl₂-   ethyl acetate: AcOEt or EtOAc-   methanol: MeOH-   trifluoroacetate: TFA-   triethylamine: Et₃N or TEA-   butoxycarbonyl: n-Boc or Boc-   nuclear magnetic resonance spectroscopy: NMR-   liquid chromatography mass spectrometry: LCMS-   high resolution mass spectrometry: HRMS-   milliliters: mL-   millimoles: mmol-   microliters: μl-   grams: g-   milligrams: mg-   room temperature or rt (ambient): about 25° C.

Compounds of this invention can be prepared by known methods fromstarting materials either known in the art or prepared by methods knownin the art.

Compounds of the present invention can be prepared by several methods.Non-limiting examples of suitable methods are illustrated in the schemesbelow.

Examples

The compounds of the present invention can be prepared through thegeneral routes described below.

Synthesis of pyrazolo[1,5-a]pyridines (Formula III) is described belowin Scheme 1.

-   R is defined above.

Alternative synthesis of intermediate 2 is illustrated in Scheme 1a:

Generally, one method of preparing a pyrazolo[1,5-a]pyridine involvescombining (1H-Pyrazol-3-yl)-acetonitrile with2-Benzylidene-malononitrile to form a 7-amino substitutedpyrazolo[1,5-a]pyridine that is further reacted with the appropriatealdehyde to achieve the target pyrazolo[1,5-a]pyridine as shown inSchemes 1 and 1a.

Another method to synthesize a pyrazolo[1,5-a]pyridine is illustrated inScheme 1b.

Scheme 1c illustrates an alternative route to intermediate 17,3-cyano-4-phenyl pyridine.

Scheme 1d illustrates a chlorinated form of intermediate 17,3-cyano-4-phenyl pyridine.

An alternative route to target pyrazolo[1,5-a]pyridine is illustrated inScheme 1e.

An unsubstituted phenyl pyridine instead of the 3-cyano-4-phenylpyridine as shown in Schemes 1b-d can be used in the synthesis of thecarbonitrile substituted target pyrazolo [1,5-a]pyridine. In which case,the cyano group is added during the last steps of the synthesis bybrominating the 4 position then substituting the bromine with acarbonitrile group as shown in Scheme 1e.

A 4-methylamino pyrazolo [1,5-a]pyridine derivative is formed byreducing the 4-cyano group using lithium aluminum hydride as shown inscheme 1f.

Synthesis of other target pyrazolo[1,5-a]pyridine compounds isillustrated in Scheme 1G.

Various benzyl derivatives of the target pyrazolo[1,5-a]pyridinecompounds can be prepared by reducing the 3-cyano group of the3-cyano-4-phenyl pyridine by treating the compound with lithium aluminumhydride forming the methyl amino derivative, which is furtherderivatized as shown in Scheme 1G then processed using the synthesisdescribed above in Schemes 1b-1d.

A general, synthesis of imidazo[1,2-a]pyridine (Formula V) is describedbelow in Scheme 2.

Treatment of the starting 2-amino-5-bromopyridine 86 with nitric acidand sulfuric acid introduces a nitro group, which is converted to anamine by a reaction with SnCl₂. Treatment of this5-Bromo-4-nitro-pyridin-2-ylamine 90 with 2-Bromo-1,1-diethoxy-ethane 89in the presence of hydrochloric acid followed by sodium bicarbonateyields 6-Bromo-imidazo[1,2-a]pyridin-8-ylamine 91. The amino group isacetylated by treating it with acetyl chloride in the presence ofpyridine, which upon addition of the aromatic boronic acid 93 inPd(PPh₃)₃, K₃PO₄, and dimethylether-water furnishes intermediateN-[6-(2-Chloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-acetamide 94.Treatment of compound 94 with NBS gives rise to intermediateN-[3-Bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-acetamide 95,which in the presence of ethanolic hydrochloric acid forms intermediate3-Bromo-6-(2-chloro-phenyl)-imidazol[1,2-a]pyridin-8-ylamine 96, whichreacts with the appropriate aldehyde in zinc chloride and sodiumcyanoborohydride to give the desired intermediate amine 97. Treatmentwith bromine and acetic acid yields the desired3,5-Dibromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridin-8-ylaminederivative 98, which is converted to the target compound8-Amino-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridine-5-carbonitrilederivative 99.

An alternative route to synthesize the carbonitrile derivative ofimidazo[1,2-a]pyridine is illustrated in Scheme 2a.

Treatment of intermediateN-[6-(2-Chloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-acetamide 94 withsodium hydroxide or ethanolic hydrochloric acid converts the acetamideto its amine, which is then treated with an appropriate aldehyde in thepresence of zinc chloride and cyanosodiumborohydride giving rise to aderivatized amine intermediate 102. Intermediate 102 is lithiated andiodated at position 5 then treated with potassium cyanide to replace theiodide group with a carbonitrile group in intermediate 104. Treatment of104 with NBS yields brominated target compound8-Amino-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridine-5-carbonitrilederivative 99.

A general route to synthesize the amino derivative ofimidazo[1,2-a]pyridine is illustrated in Scheme 2b.

The iodated intermediate 103 is converted to an amine by first treating103 with benzhydrylideneamine, Pd(OAc)2,(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP), cesium carbonate,and toluene to form intermediate 107, which is then treated with NBS tobrominate the imidazo group to form intermediate 108. Intermediate 108is converted to the amine by treatment with ammonia and sodium acetateto yield the amine derivative of the imidazo[1,2-a]pyridine targetcompound 109.

A general route to synthesize the methyl amino derivative ofimidazo[1,2-a]pyridine is illustrated in Scheme 2c.

The carbonitrile group of the 8-amino derivative ofimidazo[1,2-a]pyridine-5-carbonitrile is reduced to a methylamino groupusing lithium aluminum hydride to yield intermediate 111. Each of theamino substituents of intermediate 111 are protected with atertbutyloxycarbonyl (BOC) protection group by a reaction with a BOCanhydride reagent. The imidazo ring of the protected intermediate isbrominated with NBS then the compound is deprotected with sulfuric acidin dioxane to yield target compound5-aminomethyl-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyridine-8-ylaminederivative 114.

A general, synthesis of imidazo[1,5-a]pyrazine (Formula VI) is describedbelow in Scheme 3.

Treatment of the commercially available starting compound3-amino-pyrazine-2-carboxylic acid methyl ester 115 with bromineprovides the 6-bromo derivative of compound 115, which undergoes aSuzuki coupling reaction by treating compound 115 with an aryl boronicacid in the presence of the triethyl amine, palladium diacetate,1,1-bis(diphenyl-phosphine)ferrocene, dimethyl formamide, palladiumtetra triphenyl phosphate, potassium phosphate, and benzene forming3-amino-6-(2 chlorophenyl)-pyrazine-2-carboxylic acid methylester. Themethyl ester is hydrolyzed in aqueous sodium hydroxide leaving thecarboxylic acid 119, which is replaced by a bromine substituent aftertreatment with sodium diacetate and bromine in acetic acid it iscombined with 2-bromo-1,1-diethoxy-ethane 121 in aqueous hydrobromicacid yielding imidopyrazine 122. The imidazo group is brominated bytreatment with NBS in chloroform to yield intermediate 123. Selectivereplacement of the bromine with an amine occurs by treatment ofintermediate 123 with ammonium hydroxide or ammonia in methanol formingintermediate compound 124. Intermediate 124 is reacted with theappropriate aldehyde in the presence of zinc chloride followed by cyanosodium borohydride to give rise to intermediate3-Bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyrazin-8-ylaminederivative125. Intermediate 125 is further brominated at position 5 by treatmentwith bromine in acetic acid to provide intermediate 126. Intermediate126 is converted to target compound8-Aminoderivative-3-bromo-6-(2-chloro-phenyl)-imidazo[1,2-a]pyrazine-5-carbonitrile127 after treatment with potassium or copper cyanide.

Alternative route to synthesis of intermediate 124 is illustrated inScheme 3a.

Treatment of compound 122 with benzhydrylideneamine in the presence ofpalladium diacetate, BINAP, cesium carbonate, and toluene yieldsintermediate 129, which is brominated at its imidazo ring by treatmentwith NBS in acetonitrile to yield intermediate 130. Intermediate 130 isaminated by using ammonia in sodium acetate to form intermediate 124.

Route to the amino derivative of imidazo [1,5-a]pyrazine is illustratedin Scheme 3b.

Treatment of intermediate 126 with saturated ammonia in methanolselectively replaces the bromine group of position 5 with an amino groupyielding the target amino substituted imidazo [1,5-a]pyrazine.

Route to the methyl amino derivative of imidazo [1,5-a]pyrazine isillustrated in Scheme 3c.

The cyano substituted imidazo [1,5-a]pyrazine 127 is treated withlithium aluminum hydride which reduces both the carbonitrile group tothe target methyl amino substituted imidazo [1,5-a]pyrazine and removesthe 3-brono groups which is subsequently re-introduced with NBS toafford 135.

A general, synthesis of pyrazolo [1,5-c]pyrimidine (Formula IV) isdescribed below in Scheme 4.

Combination of the starting Benzyl-hydrazine 136 with Oxo-acetic acidethyl ester 137 gives rise to intermediate (Benzyl-hydrazono)-aceticacid ethyl ester 138, which is chlorinated by treatment withN-chloromethyl succinamide or tertiarybutoxy chloride to formintermediate 139. The combination of Intermediate 139 with vinyl benzene140 forms the ester intermediate1-Benzyl-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester141. Saponification of the ester intermediate 141 gives rise tointermediate 1-Benzyl-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid142 that gives rise to the cyanoamine intermediate 143 when heated tohigh temperatures in anhydrous dimethylformamide. Upon further reactionof intermediate 143 with diethyl oxalate 144 affords the intermediate2,3-dioxo-4-cyanopyrrolidine 145, which forms intermediate1-Benzyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylicacid amide 146 under acidic conditions and an amino group replaces theOH group forming intermediate4-Amino-1-benzyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acidamide 147. Treatment of Intermediate 147 with dimethylformamide andsodium nitrite formsintermediate1-Benzyl-4-imino-5-oxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylicacid amide 148 and a combination with compound But-2-ynedioic aciddiethyl ester 149 forms an intermediate7-Benzyl-9-carbamoyl-6-oxo-8-phenyl-1,2,7-triaza-spiro[4.4]nona-1,3,8-triene-3,4-dicarboxylicacid diethyl ester 150, which converts to intermediate6-Benzyl-4-carbamoyl-7-oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-2,3-dicarboxylicacid diethyl ester 151. Reflux of intermediate 151 in the presence ofthe acid gives rise to intermediate6-Benzyl-7-oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-4-carboxylicacid amide 152. Heating formic acid and ammonium ion mixture in methanoland 10% Pd—C to reflux eliminates the benzyl group forming intermediate7-Oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-4-carboxylic acidamide 153. Reflux of 153 in phosphorous oxychloride forms intermediate7-Chloro-5-phenyl-pyrazolo[1,5-c]pyrimidine-4-carbonitrile 154 andtreatment with the appropriate amine represented as Y—NH₂ results in asubstitution of the chloride ion of 154 with the described aminederivative intermediate 155. Treatment of 155 with NBS forms targetcompound 7-Aminoderivative-3-bromo-5-phenyl-pyrazolo[1,5-c]pyrimidine-4-carbonitrile156.

A route to the synthesis of a methyl amino pyrazolo [1,5-c]pyrimidine isdescribed below in Scheme 4a.

Treatment of intermediate 157 with lithium aluminum hydride followed byNBS forms target compound4-Aminomethyl-3-bromo-5-phenyl-pyrazolo[1,5-c]pyrimidin-7-ylaminederivative 159.

A general, synthesis of 2H-indazoles (Formula VII) is described below inScheme 5.

Reflux of a combination of starting compounds4-Bromo-2-methyl-6-nitro-phenylamine 160 and aromatic boronic acid 161in the presence of Pd(Ph₃P)₄, K₃PO₄, Benzene, dimethylformamide givesrise to intermediate 2′-Fluoro-5-methyl-3-nitro-biphenyl-4-ylamine 162.Tricyclic intermediate 5-(2-Fluoro-phenyl)-7-nitro-2H-indazole 165 isformed from intermediate 162 by using one of two reactions. One reactioninvolves treating intermediate 162 with sodium nitrite, acetic acid, andhydrochloric acid to form intermediateN-(2′-Fluoro-5-methyl-3-nitro-biphenyl-4-yl)-hydroxylamine 163 thenrefluxing intermediate 163 in benzene to form intermediate 165. Thesecond reaction involves treating intermediate 162 with HBF₄ and sodiumnitrite forming intermediate2′-Fluoro-5-methyl-3-nitro-biphenyl-4-diazonium⁺BE₄ ⁻164 then treatingintermediate 164 with potassium acetate and 18-Crown-6 in chloroform toform intermediate 165. Intermediate 165 is treated with Pd—C in ethanoland hydrogen, which reduces the nitro substituent of intermediate 165 toan amine forming intermediate 5-(2-Fluoro-phenyl)-2H-indazol-7-ylamine166. Treatment of intermediate 166 with Bu₄NBr₃ (TBATB) and DMF-H₂Obrominated intermediate 166 to form intermediate4-Bromo-5-(2-fluoro-phenyl)-2H-indazol-7-ylamine 167. The bromine ofintermediate 167 is replaced with a carbonitrile group by refluxing incoppercyanide in pyridine forming intermediate7-Amino-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile 168. Reductivealkylation of intermediate 168 is accomplished by treating intermediate168 with the appropriate aldehyde in the presence of zinc chloride andsodium cyano borohydride forming intermediate 169, which is brominatedby treatment with Bu₄NBr₃ (TBATB) in DMF-H₂O forming target compound7-Amino-3-bromo-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrilederivative 170

Route to the amino methyl 2H-indazole derivative is illustrated inScheme 5a.

The carbonitrile group of Intermediate 169 is reduced with lithiumaluminum hydride yielding the methylamino substituent group ofintermediate 171. Intermediate 171 is brominated by treatment withBu₄NBr₃ (TBATB) and DMF-H₂O to form target compound4-Aminomethyl-3-bromo-5-(2-fluoro-phenyl)-2H-indazol-7-ylamine 172.

Route to the amino 2H-indazole derivative is illustrated in Scheme 5b.

Intermediate 167 undergoes reductive alkylation to form compoundintermediate 173. The bromine group is replaced with an aminesubstituent by refluxing in ammonia and methanol to form intermediate174. The imidazo ring of intermediate 174 is bromintated by treatmentwith TBATB and dimethylformamide in water to form target compound3-Bromo-5-(2-fluoro-phenyl)-2H-indazole-4,7-diamine derivative 175.

Preparative Examples: Preparative Example 1

Step A:

A mixture of the starting material prepared as in WO2004/026877 (640 mg,2.78 mmol), 3-(aminomethyl)pyridine (360 mg, 3.34 mmol),diisopropylethylamine (3.2 mL), and anhydrous dioxane (8 mL) was stirredat 90° C. under N₂ for 72 hr. The solvent was evaporated and the residuewas purified by column chromatography on silica gel with CH₂Cl₂/7N NH₃in MeOH (40:1). White solid (720 mg, 86%) was obtained. LCMS: MH⁺=302.

Step B

A solution of N-bromosuccinimide (“NBS”) (424 mg, 2.36 mmol) inanhydrous CH₃CN (20 mL) was added under N₂ to a stirred solution of theproduct of Step A (710 mg, 2.36 mmol) in anhydrous CH₃CN (20 mL) andCH₂Cl₂ (20 mL). The mixture was stirred at 25° C. for 2 hr and thesolvent was then evaporated. Chromatography on silica gel withEtOAc/MeOH (20:1) afforded a white solid (710 mg, 79%). LCMS: M⁺=380,M.P.=169-170° C.

Step C:

A mixture of the product from Step B (500 mg, 1.31 mmol mmol), Zn(CN)₂(300 mg, 2.56 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16mmol), and bis(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) inanhydrous DMF (10 mL) was stirred at 140° C. under N₂ for 20 hr. Thesolvent was evaporated and the residue was purified by columnchromatography and then by preparative TLC on silica gel with PhCH₃/MeOH(10:1). A Pale orange solid (9 mg, 2%) was obtained. LCMS: MH⁺=327.

Preparative Example 2

A solution of N-bromosuccinimide (“NBS”) (2.7 mg, 0.015 mmol) inanhydrous CH₃CN (0.2 mL) was added under N₂ to a stirred solution of theproduct from Preparative Example 1, Step C (5.0 mg, 0.015 mmol) inanhydrous CH₃CN (0.5 mL). The mixture was stirred at 25° C. for 24 hrand the solvent was then evaporated. Chromatography on silica gel withPhCH₃/MeOH (7:1) afforded a colorless solid (3 mg, 48%). LCMS: M⁺=405.

Preparative Example 3

Step A:

Propargyl alcohol (10.0 g, 78 mM) was added under argon to a stirredsolution of 2.0 M Trimethylsilyl diazomethane in hexanes (89 mL, 178 mM)in anhydrous Et₂O (200 mL). The solution stirred for 11 days at 25° C.and the solvent then evaporated. Chromatography on silica gel (30×5 cm)with CH₂Cl₂/MeOH (10:1) afforded the product (3.15 g, 18%). (Jones,Reuben, JACS, 71, 3994-4000. 1949)

Step B:

SOCl₂ (3.45 mL, 47.3 mM) was added to a vigorously stirring biphasicmixture of (1H-Pyrazol-3-yl)-methanol (2.59 g, 26.4 mM) from Step A inanhydrous CH₂Cl₂ at 0° C. The mixture was stirred at 0° C. for 0.5 hrand then the solvent and excess SOCl₂ were evaporated, forming3-Chloromethyl-1H-pyrazole. The 3-Chloromethyl-1H-pyrazole was usedwithout purification for Step C. (Jones, Reuben, JACS, 71, 3994-400,1949)

Step C:

To a stirred solution of KCN (15.86 g, 243 mM) in H₂O (30 mL) at 0° C.was added dropwise over 0.33 hr, a solution of3-Chloromethyl-1H-pyrazole (3.08 g, 26.4 mM) from Step B in absoluteEtOH (62 mL). After 2.5 hours, the reaction mixture was filtered, thesolids were washed with absolute EtOH (2×50 mL), and the filtrate wasevaporated. Chromatography on silica gel (30×5 cm) with CH₂Cl₂/MeOH(97.5:2.5) afforded (1H-Pyrazol-3-yl)-acetonitrile (1.93 g, 68%).(Jones, Reuben, JACS, 71, 3994-4000, 1949)

Preparative Example 4

To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100 mg, 0.93mM) from Step C of Preparative Example 3, in absolute EtOH (4.7 mL) at25° C. was added benzylidene malononitrile (144 mg, 0.93 mM) andpiperidine (0.009 mL, 0.09 mM). The mixture then refluxed for 1.0 hr.The solvent evaporated. Chromatography on silica gel (60×2.5 cm) withCH₂Cl₂ afforded7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6 mg,14%) LCMS: MH⁺=260; HRMS: m/z 260.0938 (MH⁺), Calcd. C₁₅H₉N₅: m/z260.0936; 5_(c) (DMSO) CH: 99.0, 128.5, 128.5, 128.8, 128.8, 129.8,145.4; C: 75.4, 86.9, 115.5, 116.0, 134.8, 138.9, 148.1, 149.4.

Preparative Example 5

To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (1.56 g, 14.5mM) from Preparative Example 3 Step C in absolute EtOH (73 mL) at 25° C.was added o-chlorobenzylidene malononitrile (2.74 g, 14.5 mM) andpiperidine (0.14 mL, 1.45 mM). The mixture then refluxed for 1.75 hr.The solvent evaporated. Chromatography on silica gel (30×5 cm) withCH₂Cl₂ afforded7-Amino-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile(0.62 g, 15%). HRMS: m/z 293.0472 (M⁺), Calcd. C₁₅H₈N₅Cl₁: m/z 293.0468;δ_(C) (CDCl₃) CH: 99.3, 127.6, 129.6, 130.8, 131.6, 145.5; C: 75.7,86.9, 114.8, 115.1, 131.5, 133.8, 138.4, 145.6, 149.2.

Preparative Example 6

NaH (52 mg, 2 mM) was added to a stirred solution of7-Amino-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile(0.30 g, 1 mM) from Preparative Example 5 in anhydrous DMF (6 mL) at 25°C. After 0.5 hr, 3-Picolinyl chloride hydrochloride (167 mg, 1 mM) wasadded. The mixture was stirred at 25° C. for 0.5 hr and then at 60° C.for 17 hr. The mixture was added to CH₂Cl₂ (400 mL) and washed withsaturated NaHCO₃ (60 mL). Chromatography on silica gel (15×5 cm)afforded unreacted starting material (121 mg, 41%) and5-(2-Chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile147 mg, 37%). LCMS: MH⁺=385; HRMS: m/z 385.0967 (MH⁺) Calcd. C₂₁H₄N₆Cl₁:m/z 385.0968; δ_(C) (CDCl₃) CH₂: 45.5; CH: 100.8, 124.1, 127.5, 130.3,130.5, 131.7, 135.7, 144.8, 149.4, 150.2; C: 76.6, 91.7, 114.5, 115.8,133.0, 133.5, 138.4, 146.5, 146.7.

Preparative Example 7

N-Bromosuccinimde (64 mg, 0.34 mM) was added to a stirred solution ofPreparative Example 6,5-(2-Chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile,(140 mg, 0.34 mM) in anhydrous CH₂Cl₂ (7 mL) and CH₃CN (7 mL) at 25° C.The mixture stirred at 25° C. for 90 hr. The mixture was filteredthrough a medium sintered glass filter and the solid washed with CH₂Cl₂(3×25 mL). The filtrate was evaporated and the residue waschromatographed on silica gel (15×2.5 cm) with CH₂Cl₂ and then a 0.5%solution of (10% NH₄OH in MeOH) in CH₂Cl₂ to afford crude3-Bromo-5-(2-chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile(59.5 mgs). This sample was further purified by a CH₂Cl₂/saturated aq.NaHCO₃ extraction and chromatographed on silica gel (15×2 cm) with 0.5%solution of (10% NH₄OH in MeOH) in CH₂Cl₂, followed by an Et₂O/H₂Oextraction, and finally a Prep TLC on four 20×20 cm 250 micron silicagel plates developed in 2.0% solution of (10% NH₄OH in MeOH) in CH₂Cl₂.This afforded3-Bromo-5-(2-chloro-phenyl)-7-[(pyridin-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile.LCMS: MH⁺=465; δ_(C) (DMSO) CH₂: 43.7; CH: 123.5, 127.6, 129.6, 130.7,131.7, 134.8, 145.6, 147.7, 148.0; C: 75.9, 86.3, 87.7, 113.4, 115.6,131.5, 133.3,133.7, 147.0, 148.6.

Example 1 Step A

A mixture of the starting material prepared as in WO2004/026877 (640 mg,2.78 mmol), 3-(aminomethyl)pyridine (360 mg, 3.34 mmol),diisopropylethylamine (3.2 mL), and anhydrous dioxane (8 mL) was stirredat 90° C. under N₂ for 72 hr. The solvent was evaporated and the residuewas purified by column chromatography on silica gel with CH₂Cl₂/7N NH₃in MeOH (40:1). White solid (720 mg, 86%) was obtained. LCMS: MH⁺=302.

Step B

A solution of N-bromosuccinimide (“NBS”) (424 mg, 2.36 mmol) inanhydrous CH₃CN (20 mL) was added under N₂ to a stirred solution of thestarting material from Step A (710 mg, 2.36 mmol) in anhydrous CH₃CN (20mL) and CH₂Cl₂ (20 mL). The mixture was stirred at 25° C. for 2 hr andthe solvent was then evaporated. Chromatography on silica gel withEtOAc/MeOH (20:1) afforded white solid (710 mg, 79%). LCMS: M⁺=380,M.P.=169-170° C.

Step C:

A mixture of the product from Step B (500 mg, 1.31 mmol mmol), Zn(CN)₂(300 mg, 2.56 mmol), tris(dibenzylideneacetone)dipalladium (150 mg, 0.16mmol), and bis(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) inanhydrous DMF (10 mL) was stirred at 140° C. under N₂ for 20 hr. Thesolvent was evaporated and the residue was purified by columnchromatography and then by preparative TLC on silica gel with PhCH₃/MeOH(10:1). Pale orange solid (9 mg, 2%) was obtained. LCMS: MH⁺=327.

Examples 2-6

The compounds of column 4 shown in Table 2 are prepared by essentiallythe same procedure set forth in Example 1, only substituting thecompound shown in Column 2 and the amine shown in column 3. The cyanosubstituent of the products shown in column 4 are reduced to amethylamino group as shown in column 5 using lithium aluminum anhydrideas illustrated in scheme If above. Example 6 is the product of Example 1that also has been reduced in lithium aluminum anhydride.

TABLE 2 Example Column 2 Column 3 Column 4 Column 5 2

3

4

5

6

Example 7

A solution of N-bromosuccinimide (“NBS”) (2.7 mg, 0.015 mmol) inanhydrous CH₃CN (0.2 mL) was added under N₂ to a stirred solution of theproduct from Preparative Example 1, Step C (5.0 mg, 0.015 mmol) inanhydrous CH₃CN (0.5 mL). The mixture was stirred at 25° C. for 24 hrand the solvent was then evaporated. Chromatography on silica gel withPhCH₃/MeOH (7:1) afforded a colorless solid (3 mg, 48%). LCMS: M⁺=405.

Examples 8-11

The compounds of column 3 shown in Table 3 are prepared by essentiallythe same procedure set forth in Example 7, only substituting thecompound shown in Column 2. Again, the cyano substituent of the productsshown in column 3 are reduced to a methylamino group as shown in column4 using lithium aluminum anhydride as illustrated in scheme 1f above.Example 11 is the methylamino substituted version of Example 7 above:

TABLE 3 Examples Column 2 Column 3 Column 4  8

 9

10

11

Example 12

To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100 mg, 0.93mM) in absolute EtOH (4.7 mL) at 25° C. was added benzylidenemalononitrile (144 mg, 0.93 mM) and piperidine (0.009 mL, 0.09 mM). Themixture then refluxed for 1.0 hr. The solvent evaporated. Chromatographydone on silica gel (60)(2.5 cm) with CH₂Cl₂ afforded7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6 mg,14%) LCMS: MH⁺=260; HRMS: m/z 260.0938 (MH), Calcd. C₁₅H₉N₅: m/z260.0936; δ_(C) (DMSO) CH: 99.0, 128.5, 128.5, 128.8, 128.8, 129.8,145.4; C: 75.4, 86.9, 115.5, 116.0, 134.8, 138.9, 148.1, 149.4.

Example 13

Boc-anhydride and NaOH was added to the product of Example 12 in orderto protect its amine as an N-Boc derivative. A solution ofN-bromosuccinimide (“NBS”) in anhydrous CH₃CN is added and stirred underN₂ in anhydrous CH₃CN. The mixture is stirred at 25° C. for 24 hr andthe solvent is then evaporated. The Boc group may be removed from theamine by stirring with sulfuric acid in dioxane to yield the product7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile.

Examples 14-20

The free amine of the product of Example 13 is stirred in the presenceof ZnCl₂ and NaBH₃CN with the appropriate aldehyde as shown in Column 2of Table 4 below to produce the various amino derivatives illustrated incolumn 3:

TABLE 4 Examples: Column 2 Column 3 14

15

16

17

18

19

20

Example 21-27

The amine derivatives of the compounds of this invention are prepared byfollowing a series of reactions in the order described below. Thestarting material is the same as that of Scheme 2 above (compound 86).The series of reactions illustrated in Scheme 2 from compound 86 tocompound 94 are followed. Next, compound 94 is used according to theseries of reactions illustrated in Scheme 2a, beginning with compound 94to compound 103. Finally, compound 103 is used according to the seriesof reactions illustrated in Scheme 2b. The series of reactions of Scheme2b are also illustrated and described below:

The iodated intermediate is converted to an amine by first treating itwith benzhydrylideneamine, Pd(OAc)2,(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (BINAP), cesium carbonate,and toluene to form the 5,8-diamine intermediate, which is then treatedwith NBS to brominate the imidazo group. The brominated 5,8-diamineintermediate is converted to the amine by treatment with NH₂OH and NaOActo yield the amine derivative of the imidazo[1,2-a]pyridine targetcompounds.

Alternatively, the amine derivatives are formed by following essentiallythe same procedure described in Scheme 3b wherein intermediates thatcorrespond to intermediate 126 for each compound of this invention aretreated with saturated ammonia in methanol, which selectively replacesthe bromine group with an amino group yielding the target aminosubstituted compound as illustrated below:

Some representative examples are illustrated in column 2 of Table 5below:

TABLE 5 Examples Column 2 21

22

23

24

25

26

27

ASSAY: The assay on the compounds of the present invention may beperformed as follows.

BACULOVIRUS CONSTRUCTIONS: Cyclin E is cloned into pVL1393 (Pharmingen,La Jolla, Calif.) by PCR, with the addition of 5 histidine residues atthe amino-terminal end to allow purification on nickel resin. Theexpressed protein is approximately 45 kDa. CDK2 is cloned into pVL1393by PCR, with the addition of a haemaglutinin epitope tag at thecarboxy-terminal end (YDVPDYAS). The expressed protein is approximately34 kDa in size.

ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclin E andCDK2 are co-infected into SF9 cells at an equal multiplicity ofinfection (MOI=5), for 48 hrs. Cells are harvested by centrifugation at1000 RPM for 10 minutes, then pellets lysed on ice for 30 minutes infive times the pellet volume of lysis buffer containing 50 mM Tris pH8.0, 150 mM NaCl, 1% NP40, 1 mM DTT and protease inhibitors (RocheDiagnostics GmbH, Mannheim, Germany). Lysates are spun down at 15000 RPMfor 10 minutes and the supernatant retained. 5 ml of nickel beads (forone liter of SF9 cells) are washed three times in lysis buffer (QiagenGmbH, Germany). Imidazole is added to the baculovirus supernatant to afinal concentration of 20 mM, then incubated with the nickel beads for45 minutes at 4° C. Proteins are eluted with lysis buffer containing 250mM imidazole. Eluate is dialyzed overnight in 2 liters of kinase buffercontaining 50 mM Tris pH 8.0, 1 mM DTT, 10 mM MgCl2, 100 uM sodiumorthovanadate and 20% glycerol. Enzyme is stored in aliquots at −70° C.

IN VITRO KINASE ASSAY: Cyclin E/CDK2 kinase assays are performed in lowprotein binding 96-well plates (Corning Inc, Corning, N.Y.). Enzyme isdiluted to a final concentration of 50 □g/ml in kinase buffer containing50mM Tris pH 8.0, 10 mM MgCl₂, 1 mM DTT, and 0.1 mM sodiumorthovanadate. The substrate used in these reactions is a biotinylatedpeptide derived from Histone H1 (from Amersham, UK). The substrate isthawed on ice and diluted to 2 μM in kinase buffer. Compounds arediluted in 10% DMSO to desirable concentrations. For each kinasereaction, 20 μl of the 50 μg/ml enzyme solution (1 μg of enzyme) and 20μl of the 2 μM substrate solution are mixed, then combined with 10 μl ofdiluted compound in each well for testing. The kinase reaction isstarted by addition of 50 μl of 2 μM ATP and 0.1 μCi of 33P-ATP (fromAmersham, UK). The reaction is allowed to run for 1 hour at roomtemperature. The reaction is stopped by adding 200 μl of stop buffercontaining 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg/mlstreptavidine coated SPA beads (from Amersham, UK) for 15 minutes. TheSPA beads are then captured onto a 96-well GF/B filter plate(Packard/Perkin Elmer Life Sciences) using a Filtermate universalharvester (Packard/Perkin Elmer Life Sciences.). Non-specific signalsare eliminated by washing the beads twice with 2M NaCl then twice with 2M NaCl with 1% phosphoric acid. The radioactive signal is then measuredusing a TopCount 96 well liquid scintillation counter (fromPackard/Perkin Elmer Life Sciences).

IC₅₀ DETERMINATION: Dose-response curves are be plotted from inhibitiondata generated, each in duplicate, from 8 point serial dilutions ofinhibitory compounds. Concentration of compound is plotted against %kinase activity, calculated by CPM of treated samples divided by CPM ofuntreated samples. To generate IC₅₀ values, the dose-response curves arethen fitted to a standard sigmoidal curve and IC₅₀ values are derived bynonlinear regression analysis.

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

1. A compound represented by the structural formula:

wherein: X is C or N; Y is selected from the group consisting of CN,NH₂, and CH₂NH₂; R¹ is selected from the group consisting of H, halogen,R⁹, NH₂, CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, CF₃,heterocyclylalkyl, arylalkyl, heteroarylalkyl, heterocyclyalkylalkyl,cycloalkyl, cycloalkylalkyl, C(O)OR⁴, alkyl substituted with 1-6 R⁹groups which can be the same or different and are independently selectedfrom the list of R⁹ shown later below,

wherein the aryl in the above-noted definitions for R¹ can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of halogen, CN, NH₂, —OR⁵, SR⁵, —CH₂OR⁵,—C(O)R⁵, —SO₃H, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —NR⁵R⁶, —C(O)NR⁵R⁶, —CF₃, and—OCF₃; R² is selected from the group consisting of H, halogen, —NR⁵R⁶,—C(O)OR⁴, —C(O)NR⁵R⁶, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl,

wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl,arylalkyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R² andheterocyclyl moieties whose structures are shown immediately above forR² can be unsubstituted or optionally independently substituted with oneor more moieties which can be the same or different, each moiety beingindependently selected from the group consisting of halogen, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, CF₃, CN, —OCF₃, —(CR⁴R⁵)_(n)OR⁵,—OR⁵, —R⁵OR⁵, —NR⁵R⁶, —(CR⁴R⁵)_(n)NR⁵R⁶, —C(O₂)R⁵, —C(O)R⁵, —C(O)NR⁵R⁶,SR⁶, —S(O₂)R⁶, —S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and—N(R⁵)C(O)NR⁵R⁶; R₃ is selected from the group consisting of a halogen,CN, amino, alkylamino, cycloalkylamino, arylalkylamino, heteroarylamino,heteroarylalkylamino, hydroxyalkylamino, heterocycloalkylalkylamino,wherein each of said amino, alkylamino, cycloalkylamino, arylalkylamino,heteroarylamino, heteroarylalkylamino, hydroxyalkylamino, andheterocycloalkylalkylamino can be unsubstituted or optionallyindependently substituted with one or more moieties, which can be thesame or different, each moiety being independently selected from thegroup consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, heteroarylalkyl, heterocycloalkylalkyl,cycloalkylalkyl, CF₃, OCF₃, CN, —OR⁵, —NR⁵R⁶, —C(R⁴R⁵)_(n)OR⁵, —C(O₂)R⁵,—C(O)R⁵, —C(O)NR⁵R⁶, —SR⁶, —S(O₂)R⁷, —S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; R⁴ is H, halogen, CN or alkyl; R⁵ is Hor alkyl; R⁶ is selected from the group consisting of H, alkyl, aryl,arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, andheteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl,cycloalkyl, heterocyclolalkyl, heteroaryl, and heteroarylalkyl can beunsubstituted or optionally substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of halogen, alkyl, aryl, cycloalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵, —C(O)R⁵,—C(O)NR⁵R¹⁰, —SO₃H, —SR¹⁰, —S(O₂)R⁷, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R¹⁰; R¹⁰ is selected from the groupconsisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl,heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl,arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkylcan be unsubstituted or optionally substituted with one or more moietieswhich can be the same or different, each moiety being independentlyselected from the group consisting of halogen, alkyl, aryl, cycloalkyl,CF₃, OCF₃, CN, —OR⁵, —NR⁴R⁵, —N(R⁵)Boc, —(CR⁴R⁵)_(n)OR⁵, —C(O₂)R⁵,—C(O)NR⁴R⁵, —C(O)R⁵, —SO₃H, —SR^(S), —S(O₂)R⁷, —S(O₂)NR⁴R⁵,—N(R⁵)S(O₂)R⁷, —N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁴R⁵; optionally (i) R⁵ andR¹⁰ in the moiety —NR⁵R¹⁰, or (ii) R⁵ and R⁶ in the moiety —NR⁵R⁶, maybe joined together to form a cycloalkyl or heterocycloalkyl moiety, witheach of said cycloalkyl or heterocycloalkyl moiety being unsubstitutedor optionally independently being substituted with one or more R⁹groups; R⁷ is selected from the group consisting of alkyl, cycloalkyl,aryl, heterocycloalkyl, heteroaryl, arylalkyl and heteroarylalkyl,wherein each of said alkyl, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, arylalkyl and heteroarylalkyl, for R⁷ can be unsubstitutedor optionally independently substituted with one or more moieties whichcan be the same or different, each moiety being independently selectedfrom the group consisting of halogen, alkyl, aryl, cycloalkyl, CF₃,OCF₃, CN, —OR⁵, —NR⁵R¹⁰, —CH₂OR⁵, —C(O₂)R⁵, —C(O)NR⁵R¹⁰, —C(O)R⁵,—S(O₂)R¹⁰, —S(O₂)NR⁵R¹⁰, —N(R⁵)S(O₂)R¹⁰, —N(R⁵)C(O)R¹⁰ and—N(R⁵)C(O)NR⁵R¹⁰; R⁸ is selected from the group consisting of R⁶,—C(O)NR⁵R¹⁰, —CH₂OR⁴, —C(O)OR⁶, —C(O)R⁷and —S(O₂)R⁷; R⁹ is selected fromthe group consisting of halogen, —CN, —NR⁵R⁶, —(CH₂)_(n)OR⁴, —C(O₂)R⁶,—C(O)NR⁵R⁶, —OR⁶, —SR⁶, —S(O₂)R⁷, —S(O₂)NR⁵R⁶, —N(R⁵)S(O₂)R⁷,—N(R⁵)C(O)R⁷ and —N(R⁵)C(O)NR⁵R⁶; m is 0 to 4; and n is 1 to
 4. 2. Thecompound of claim 1, wherein R¹ is F, Cl, Br, CF₃, CN, lower alkyl,cycloalkyl or —(CH₂)_(n)OR⁶.
 3. The compound of claim 1, wherein R² isH, lower alkyl, cycloalkyl, —C(O)OR⁴, aryl, heteroaryl, cycloalkylalkyl,

wherein said lower alkyl, aryl, cycloalkyl, heteroaryl, and theheterocyclyl moieties shown above for R² are unsubstituted or optionallyindependently substituted with one or more moieties which can be thesame or different, each moiety being independently selected from thegroup consisting of halogen, CF₃, lower alkyl, —OCH₃, —CH₂OH, —CH₂CH₂OH,and CN.
 4. The compound of claim 1, wherein R⁴ is H or CN.
 5. Thecompound of claim 1, wherein R³ is selected from the group consisting of(pyridin-3-ylmethyl)-amino, (pyridin-2-ylmethyl)-amino,(pyridin-4-ylmethyl)-amino, isopropylamino, phenylamino, Benzylamino,pyridin-3-ylamino, pyridin-2-ylamino, pyridin-4-ylamino, 2-amino-ethanoland 1-amino-ethanol.
 6. The compound of claim 1, wherein Y is selectedfrom the group consisting of CN, NH₂, and CH₂NH₂.
 7. The compound ofclaim 1, wherein Y is CN.
 8. The compound of claim 1, wherein Y is NH₂.9. The compound of claim 1, wherein Y is CH₂NH₂.
 10. The compound ofclaim 1, wherein R³ is (pyridin-3-ylmethyl)-amino.
 11. The compound ofclaim 1, wherein R³ is (pyridin-2-ylmethyl)-amino.
 12. The compound ofclaim 1, wherein R³ is (pyridin-4-ylmethyl)-amino.
 13. The compound ofclaim 2, wherein said R¹ is Br or Cl.
 14. The compound of claim 2,wherein R¹ is isopropyl or ethyl.
 15. The compound of claim 2, whereinR¹ is —CH₂OH or —CH₂OCH₃.
 16. The compound of claim 2, wherein R¹ is CN.17. The compound of claim 1, wherein R² is lower alkyl, cycloalkyl,cycloalkylalkyl, aryl, —NR⁵R⁶


18. The compound of claim 17, wherein R² is


19. The compound of claim 17, wherein R² is unsubstituted phenyl orphenyl substituted with one or more moieties selected from the groupconsisting of F, Br, Cl, OMe, CH₃ and CF₃.
 20. The compound of claim 17,wherein R² is cyclohexylmethyl.
 21. A compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 22. A compoundselected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 23. A methodof inhibiting one or more cyclin dependent kinases, comprisingadministering a therapeutically effective amount of at least onecompound of claim 1 to a patient in need of such inhibition.
 24. Amethod of treating one or more diseases associated with cyclin dependentkinase, comprising administering a therapeutically effective amount ofat least one compound of claim 1, to a patient in need of suchtreatment.
 25. The method of claim 23, wherein said cyclin dependentkinase is CDK2.
 26. The method of claim 24 wherein said disease isselected from the group consisting of: cancer of the bladder, breast,colon, kidney, liver, lung, small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin,squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acutelymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkinslymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, Burkett'slymphoma; acute and chronic myelogenous leukemia, myelodysplasticsyndrome, promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma;astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma.
 27. A method of treatingone or more diseases associated with cyclin dependent kinase, comprisingadministering to a mammal in need of such treatment an amount of a firstcompound, which is a compound of claim 1 or a pharmaceuticallyacceptable salt or solvate thereof; and an amount of at least one secondcompound, said second compound being an anti-cancer agent; wherein theamounts of the first compound and said second compound result in adesired therapeutic effect.
 28. The method of claim 27, furthercomprising radiation therapy.
 29. The method of claim 27, wherein saidanti-cancer agent is selected from the group consisting of a cytostaticagent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan(or CPT-11), camptostar, topotecan, paclitaxel, docetaxel, epothilones,tamoxifen, 5-fluorouracil, methoxtrexate, 5-Fluorouracil, temozolomide,cyclophosphamide,4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide,tipifarnib, L778,123 (a farnesyl protein transferase inhibitor), BMS214662 (a farnesyl protein transferase inhibitor), Iressa, Tarceva,antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan,gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin, Pentostatine, Vinblastine, Vincristine, Vindesine,Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin,Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase,Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, andHexamethylmelamine.
 30. A pharmaceutical composition comprising atherapeutically effective amount of at least one compound of claim 1 incombination with at least one pharmaceutically acceptable carrier. 31.The pharmaceutical composition of claim 30, additionally comprising oneor more anti-cancer agents selected from the group consisting ofcytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide,CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5-fluorouracil,temozolomide, cyclophosphamide,4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide,Zarnestra® (tipifarnib), L778,123 (a farnesyl protein transferaseinhibitor), BMS 214662 (a farnesyl protein transferase inhibitor),Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine,Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin,Mitomycin-C, L-Asparaginase, Teniposide 17□-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Dromostanolone propionate, Testolactone, Megestrolacetate,Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone,Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine,Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,Capecitabine, Reloxafine, Droloxafine, and Hexamethylmelamine.
 32. Acompound of claim 1 in isolated and purified form.